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The widely distributed Eocene mafic microgranular enclaves in the Lhasa Terrane of southern Tibet carry important information regarding crust–mantle interactions in collisional zones. Here, we report geochronological and geochemical data of granitoids and mafic enclaves from Quxu in the southern Lhasa Terrane. Zircon LA‐ICP‐MS U–Pb dating indicates that the Quxu granitoids and enclaves were synchronously emplaced at ca. 50 Ma. The granitoids are medium‐ to high‐K calc‐alkaline, metaluminous (A/CNK = 0.82–0.90) and have high Al2O3 (14.48–16.57 wt%) and low MgO (2.81–2.99 wt%). The mafic enclaves (SiO2 = 50.55–54.57 wt%) have 5.12–5.37 wt% MgO and an Mg# of 49–51, with weakly negative Eu anomalies (Eu/Eu* = 0.85–0.91). The Quxu granitoids and enclaves have similar zircon Hf isotopic compositions, with εHf(t) values ranging from +7.62 to +13.32. A comprehensive study of the data available for coeval rocks from the Gangdese Batholith indicates that the Quxu granitoids were derived from partial melting of the lower crust, while the parental magmas of the mafic enclaves were most likely derived from lithospheric mantle beneath southern Tibet. The Quxu granitoids are interpreted as the result of mixing between the lower crust‐derived melts and lithospheric mantle‐derived mafic melts, which are likely the magmatic response to the breakoff of the Neo‐Tethyan Oceanic slab at about 50 Ma.